Protein-protein interaction plays an important role in a variety of biological processes, such as angiogenesis, glucose homeostasis, mitochondrial biogenesis, adipogenesis, cell proliferation, differentiation, apoptosis, and tumorigenesis. Many human diseases are the result of abnormal protein-protein interactions involving endogenous proteins, proteins from pathogens or both. Therefore, the inhibition of these aberrant associations is clinically significant.
Currently, at least 400 individual proteins are considered to be viable drug targets, and it is estimated that the number of disease-related genes could be greater than about 10,000. Sequence analysis of these proteins shows that the majority of targets fall within a few major gene families (e.g., GPCRs, kinases, proteases and peptidases). However, protein-protein interaction presents a significant hurdle for current drug discovery efforts. In particular, targeting protein-protein interaction involving large contact areas with required specificity is challenging.
Among such protein-protein interactions, α-helices play fundamental roles in mediating protein-protein interactions. Examination of complexes of proteins with other biomolecules reveals that often one or more faces of the helix are involved in binding. As such, synthetic scaffolds that display protein-like functionality and reproduce the arrangement of key side chains on an α-helix would be invaluable as therapeutics for treating diseases associated with aberrant protein-protein interaction.
The present invention addresses this need among others.